ERK1/2 inhibition promotes robust myotube growth via CaMKII activation resulting in myoblast-to-myotube fusion

Eigler, Tamar; Zarfati, Giulia; Amzallag, Emmanuel; Sinha, Sansrity; Segev, Nadav; Zabary, Yishaia; Zaritsky, Assaf; Shakked, Avraham; Umansky, Kfir Baruch; Schejter, Eyal D.; Millay, Douglas P.; Tzahor, Eldad; Avinoam, Ori

doi:10.1016/j.devcel.2021.11.022

Cited by 58 publications

(71 citation statements)

References 94 publications

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“…9 ). Lastly, we found that pharmacological ERK1/2 inhibition, which recently has been shown to stimulate myogenesis 40 , accelerates survivin downregulation, caspase-3 activation, Nup153 degradation, and myogenin induction ( Extended Data Fig. 8d ).…”

mentioning

confidence: 63%

Caspase-mediated nuclear pore complex trimming in cell differentiation and endoplasmic reticulum stress

Cho

Hetzer

2021

Preprint

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During programmed cell death, caspases degrade 7 out of ~30 nucleoporins (Nups) to irreversibly demolish the nuclear pore complex (NPC). However, for poorly understood reasons, caspases are also activated in differentiating cells in a non-apoptotic manner. Here, we describe reversible, caspase-mediated NPC "trimming" during early myogenesis. We find that sublethal levels of caspases selectively proteolyze 4 peripheral Nups, Nup358, Nup214, Nup153, and Tpr, resulting in the transient block of nuclear export pathways. Several nuclear export signal (NES)-containing focal adhesion proteins concomitantly accumulate in the nucleus where they function as transcription cofactors. We show that one such protein, FAK (focal adhesion kinase), drives a global reconfiguration of MBD2 (methyl CpG binding domain protein 2)-mediated genome regulation. We also observe caspase-mediated NPC trimming during neurogenesis and endoplasmic reticulum (ER) stress. Our results illustrate that the NPC can be proteolytically regulated in response to non-apoptotic cues, and call for a reassessment of the death-centric view of caspases.

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confidence: 63%

Caspase-mediated nuclear pore complex trimming in cell differentiation and endoplasmic reticulum stress

Cho

Hetzer

2021

Preprint

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“…However, after examining in detail the expression of which genes are downregulated under short-term HS, we found that the expression of gene clusters for BMP-signaling, ERK1/2-signaling, and pathways involved in response to TGF-β is suppressed ( Table 1 ). According to literature data, suppression of the activity of these signaling pathways leads to premature myogenic differentiation [ 32 , 33 ]. At the early stages of SCs activation, BMP signaling pathway promotes an increase of the pool of proliferating cells and prevents premature differentiation in myoblasts [ 33 ].…”

Section: Discussionmentioning

confidence: 99%

“…It is also known that a decrease in the activity of the ERK1/2 signaling pathway leads to a reduction in the proliferation rate of myoblasts [ 34 ]. In addition, it has been shown that inhibition of the ERK1/2 signaling pathway leads to the activation of calcium-dependent mechanisms causing robust differentiation of activated SCs [ 32 ]. In the present study, we observed a decrease in the expression of genes of the ERK1/2 pathway in myoblasts isolated from the soleus muscle after 1 day of HS ( Table 1 ).…”

Section: Discussionmentioning

confidence: 99%

“…It can be assumed that, just as in the case of soleus muscle fibers [ 48 ], the accumulation of calcium ions occurs in SCs under unloading conditions. It was previously shown that the activation of calcium-dependent signaling pathways can lead to rapid differentiation of activated myoblasts [ 32 ]. It can be suggested that under unloading conditions the accumulation of calcium ions in soleus-derived myoblasts may result in significant changes in the regulation of both cell proliferation and cell differentiation.…”

Section: Discussionmentioning

confidence: 99%

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Cultured Myoblasts Derived from Rat Soleus Muscle Show Altered Regulation of Proliferation and Myogenesis during the Course of Mechanical Unloading

Komarova

Rozhkov

Ivanova

et al. 2022

IJMS

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The structure and function of soleus muscle fibers undergo substantial remodeling under real or simulated microgravity conditions. However, unloading-induced changes in the functional activity of skeletal muscle primary myoblasts remain poorly studied. The purpose of our study was to investigate how short-term and long-term mechanical unloading would affect cultured myoblasts derived from rat soleus muscle. Mechanical unloading was simulated by rat hindlimb suspension model (HS). Myoblasts were purified from rat soleus at basal conditions and after 1, 3, 7, and 14 days of HS. Myoblasts were expanded in vitro, and the myogenic nature was confirmed by their ability to differentiate as well as by immunostaining/mRNA expression of myogenic markers. The proliferation activity at different time points after HS was analyzed, and transcriptome analysis was performed. We have shown that soleus-derived myoblasts differently respond to an early and later stage of HS. At the early stage of HS, the proliferative activity of myoblasts was slightly decreased, and processes related to myogenesis activation were downregulated. At the later stage of HS, we observed a decrease in myoblast proliferative potential and spontaneous upregulation of the pro-myogenic program.

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“…The copyright holder for this preprint this version posted July 10, 2022. ; https://doi.org/10.1101/2022.07.08.499311 doi: bioRxiv preprint and during muscle regeneration (Eigler et al, 2021).…”

Section: Introductionmentioning

confidence: 99%

CXCR7 promotes foetal myoblast fusion at muscle fiber tips independently of Myomaker via a ß1integrin-EGFR-dependent mechanism

Nassari

Blavet

Duprez

et al. 2022

Preprint

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Muscle growth must be tightly regulated during development in order to obtain the final muscle shape. Myoblast fusion is a critical step of muscle growth, driving the formation of syncytial myofibers attaching at both ends to tendons. We investigated the role of the CXCR7 chemokine receptor in foetal muscle growth during chicken limb development. We show that CXCR7 displays a regionalized expression at the tips of myofibers close to tendons in foetal limb muscles, which is exclusive to the central location of the fusion gene MYOMAKER (TMEM8C in chicken) in foetal muscles. CXCR7 promotes myoblast fusion independently of TMEM8C in chicken limb muscles and in foetal myoblast cultures and requires EGF receptor signalling. The CXCR7 ligand, CXCL12, expressed in connective tissue, increases beta1integrin activation at the myotendinous junction and CXCR7 expression at muscle tips, resulting in a fusion promoting effect independent from a direct binding of CXCL12 to CXCR7 receptor. Our results evidence a CXCR7-dependent/TMEM8C-independent fusion mechanism at the myofiber tips that regulates muscle growth at the tendon/muscle interface during foetal myogenesis.

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ERK1/2 inhibition promotes robust myotube growth via CaMKII activation resulting in myoblast-to-myotube fusion

Cited by 58 publications

References 94 publications

Caspase-mediated nuclear pore complex trimming in cell differentiation and endoplasmic reticulum stress

Caspase-mediated nuclear pore complex trimming in cell differentiation and endoplasmic reticulum stress

Cultured Myoblasts Derived from Rat Soleus Muscle Show Altered Regulation of Proliferation and Myogenesis during the Course of Mechanical Unloading

CXCR7 promotes foetal myoblast fusion at muscle fiber tips independently of Myomaker via a ß1integrin-EGFR-dependent mechanism

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